How do commensal microbes cause disease? It is generally assumed that invasive infections produced by commensal organisms result primarily from a breakdown of host immunity. However, it is also possible that these microbes actively transition between programs of commensalism and virulence. Indeed, we have recently discovered that exposure of the human fungal commensal-pathogen C. albicans to the mammalian gut triggers a major developmental switch. This switch requires the well-studied Wor1 transcription factor, which was thought to be expressed only in rare genetic backgrounds where it promotes an epigenetic switch involved in mating. In contrast, we discovered that expression of this transcription factor can occur in wild-type cells but only when they pass through the mammalian gut. We have demonstrated that WOR1 expression within the host induces a novel switch that reprograms cell and colony morphology and confers commensal fitness. These GUT (Gastrointestinally-IndUced Transition) cells lack the functional hallmarks of sexually-competent opaque cells, which they resemble morphologically, and bona fide opaque cells are defective for commensalism. Rather, the GUT cell transcriptome appears to be optimized for the environment of the distal mammalian digestive tract. Our discovery of the GUT cell type switch offers insight into how a single microbe can transition between commensalism and invasive tissue pathogenesis. We propose to capitalize on this advance to develop the concept that a single organism can be both a commensal and a pathogen via the evolution of an adaptive switch in cell type that is triggered by changes in the host environment. To accomplish this goal, we will 1) identify nodes of a Wor1 regulatory circuit that mediate the white-GUT switch, 2) Identify the environmental signals and regulatory pathways that trigger the white-GUT switch and 3) test the hypothesis that switching is required for C. albicans to transition from a commensal to a pathogen. We anticipate that these studies will define a novel regulatory network required for commensalism, identify the signals that trigger this network and develop an understanding of its role in the ability of Candida to switch from being a commensal to pathogen. These advances are anticipated to open the door to preventative strategies that eliminate Candida from its commensal niche in high-risk patients such as premature babies and hospitalized adults on broad-spectrum antibiotic therapies.